The present invention describes novel nitrosated and/or nitrosylated taxanes, and novel compositions comprising at least one nitrosated and/or nitrosylated taxane, and, optionally, at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase and/or at least one therapeutic agent. The present invention also provides novel compositions comprising at least one taxane and at least one compound that donates, transfers or releases nitric oxide, elevates endogenous levels of endothelium-derived relaxing factor, stimulates endogenous synthesis of nitric oxide or is a substrate for nitric oxide synthase and/or at least one therapeutic agent. The compounds and compositions of the present invention can also be bound to a matrix. The present invention also provides methods for treating or preventing cardiovascular diseases and disorders, autoimmune diseases, pathological conditions resulting from abnormal cell proliferation, polycystic kidney disease, inflammatory diseases, preserving organs and/or tissues, or to inhibit wound contraction, particularly the prophylactic and/or therapeutic treatment of restenosis, by administering nitrosated and/or nitrosylated taxane or parent taxanes in combination with nitric oxide donors that are capable of releasing nitric oxide or indirectly delivering or transferring nitric oxide to targeted sites under physiological conditions.
Endothelium-derived relaxing factor (EDRF) is a vascular relaxing factor secreted by the endothelium and is important in the control of vascular tone, blood pressure, inhibition of platelet aggregation, inhibition of platelet adhesion, inhibition of mitogenesis, inhibition of proliferation of cultured vascular smooth muscle, inhibition of leukocyte adherence and prevention of thrombosis. EDRF has been identified as nitric oxide (NO) or a closely related derivative thereof (Palmer et al, Nature, 327:524-526 (1987); Ignarro et al, Proc. Natl. Acad. Sci. USA, 84:9265-9269 (1987)).
Removal of the endothelium is a potent stimulus for neointimal proliferation, a common mechanism underlying the restenosis of atherosclerotic vessels after balloon angioplasty (Liu et al., Circulation, 79:1374-1387 (1989); Fems et al., Science, 253:1129-1132 (1991)). Balloon arterial injury results in endothelial denudation and subsequent regrowth of dysfunctional endothelium (Saville, Analyst, 83:670-672 (1958)) that may contribute to the local smooth muscle cell proliferation and extracellular matrix production that result in reocclusion of the arterial lumen. Nitric oxide dilates blood vessels (Vallance et al., Lancet, 2:997-1000 (1989)), inhibits platelet activation and adhesion (Radomski et al., Br. J Pharmacol, 92:181-187 (1987)), and nitric oxide limits the proliferation of vascular smooth muscle cells in vitro (Garg et al., J. Clin. Invest., 83:1774-1777 (1986)). Similarly, in animal models, suppression of platelet-derived mitogens decreases intimal proliferation (Fems et al., Science, 253:1129-1132 (1991)). The potential importance of endothelium-derived nitric oxide in the control of arterial remodeling after injury is further supported by recent preliminary reports in humans suggesting that systemic NO donors reduce angiographic restenosis six months after balloon angioplasty (The ACCORD Study Investigators, J. Am. Coil. Cardiol. 23:59A. (Abstr.) (1994)).
Another aspect of restenosis may simply be mechanical, e.g., caused by the elastic rebound of the arterial wall and/or by dissections in the vessel wall caused by the angioplasty procedure. These mechanical problems have been successfully addressed by the use of stents to tack-up dissections and prevent elastic rebound of the vessel thereby reducing the level of reocclusion for many patients. The stent is typically inserted by catheter into a vascular lumen and expanded into contact with the diseased portion of the arterial wall, thereby providing internal support for the lumen. No material has, however, been developed that matches the blood-compatible surface of the endothelium. In fact, in the presence of blood and plasma proteins, artificial surfaces are an ideal setting for platelet deposition (Salzman et al, Phil. Trans. R. Soc. Lond., B294:389-398 (1981)). Exposure of blood to an artificial surface initiates reactions that lead to clotting or platelet adhesion and aggregation. Within seconds of blood contact, the artificial surface becomes coated with a layer of plasma proteins which serves as a new surface to which platelets readily adhere, become activated, and greatly accelerate thrombus formation (Forbes et al, Brit. Med. Bull., 34(2):201-207 (1978)).
Despite considerable efforts to develop nonthrombogenic materials, no synthetic material has been created that is free from this effect. In addition, the use of anticoagulant and platelet inhibition agents has been less than satisfactory in preventing adverse consequences resulting from the interaction between blood and artificial surfaces. Consequently, a significant need exists for the development of additional methods for preventing platelet deposition and thrombus formation on artificial surfaces.
There is a need in the art for effective methods of preventing and treating cardiovascular diseases and disorders, particularly, restenosis and atherosclerosis. The present invention is directed to these, as well as other, important ends.
The present invention describes novel nitrosated and/or nitrosylated taxanes and methods for preventing and/or treating cardiovascular diseases and disorders by administering one or more nitrosated and/or nitrosylated taxanes that are capable of releasing a therapeutically effective amount of nitric oxide to a targeted site effected by a cardiovascular disease or disorder. Preferably, the methods of the present invention are used for treating and/or preventing restenosis and atherosclerosis.
One embodiment of the present invention provides novel nitrosated and/or nitrosylated taxanes. The taxanes can be nitrosated and/or nitrosylated through one or more sites such as oxygen (hydroxyl condensation), sulfur (sulfhydryl condensation) and/or nitrogen. The present invention also provides compositions comprising a therapeutically effective amount of such compounds in a pharmaceutically acceptable carrier.
Another embodiment of the present invention provides compositions comprising a therapeutically effective amount of at least one taxane, that is optionally substituted with at least one NO and/or NO2 group (i.e., nitrosylated and/or nitrosated), and at least one compound that donates, transfers or releases nitrogen monoxide as a charged species, i.e., nitrosonium (NO+) or nitroxyl (NOxe2x88x92), or as the neutral species, nitric oxide (NOxe2x80xa2), and/or stimulates endogenous production of nitric oxide or EDRF in vivo and/or is a substrate for nitric oxide synthase. The present invention also provides for such compositions in a pharmaceutically acceptable carrier.
Yet another embodiment of the present invention provides compositions comprising a therapeutically effective amount of at least one taxane, that is optionally substituted with at least one NO and/or NO2 group (i.e., nitrosylated and/or nitrosated), at least one therapeutic agent, and, optionally, at least one compound that donates, transfers or releases nitrogen monoxide as a charged species, i.e., nitrosonium (NO+) or nitroxyl (NOxe2x88x92), or as the neutral species, nitric oxide (NOxe2x80xa2), and/or stimulates endogenous production of nitric oxide or EDRF in vivo and/or is a substrate for nitric oxide synthase. The invention also provides for such compositions in a pharmaceutically acceptable carrier.
Another embodiment of the present invention describes compositions and methods for making compositions comprising at least one taxane, that is optionally substituted with at least one NO and/or NO2 group (i.e., nitrosylated and/or nitrosated), and, optionally, at least one compound that donates, transfers or releases nitric oxide and/or stimulates endogenous production of nitric oxide or EDRF in vivo and/or is a substrate for nitric oxide synthase and/or at least one therapeutic agent, that are bound to a natural or synthetic matrix, which can be applied with specificity to a biological site of interest. For example, the matrix containing the nitrosated and/or nitrosylated taxane can be used to coat the surface of a medical device or instrument that comes into contact with blood (including blood components, blood products and the like) or vascular tissue.
Yet another embodiment of the present invention provides methods for treating and/or preventing cardiovascular diseases and disorders, by administering to a patient in need thereof a therapeutically effective amount of at least one nitrosated and/or nitrosylated taxane and, optionally, at least one compound that donates, transfers or releases nitric oxide as a charged species, i.e., nitrosonium (NO+) or nitroxyl (NOxe2x88x92), or as the neutral species, nitric oxide (NOxe2x80xa2), and/or stimulates endogenous production of nitric oxide or EDRF in vivo and/or is a substrate for nitric oxide synthase. The methods can further comprise administering a therapeutically effective amount of at least one therapeutic agent. Alternatively, the methods for treating and/or preventing cardiovascular diseases and disorders, can comprise administering a therapeutically effective amount of at least one nitrosated and/or nitrosylated taxane, at least one therapeutic agent, and, optionally, at least one compound that donates, transfers or releases nitric oxide as a charged species, i.e., nitrosonium (NO+) or nitroxyl (NOxe2x88x92), or as the neutral species, nitric oxide (NOxe2x80xa2), and/or stimulates endogenous production of nitric oxide or EDRF in vivo and/or is a substrate for nitric oxide synthase. The nitrosated and/or nitrosylated taxanes, nitric oxide donors, and/or therapeutic agents can be administered separately or as components of the same composition in one or more pharmaceutically acceptable carriers.
The present invention also provides methods for treating and/or preventing cardiovascular diseases and disorders by administering to a patient in need thereof a therapeutically effective amount of at least one taxane and at least one compound that donates, transfers or releases nitric oxide as a charged species, i.e., nitrosonium (NO+) or nitroxyl (NOxe2x88x92), or as the neutral species, nitric oxide (NOxe2x80xa2), and/or stimulates endogenous production of nitric oxide or EDRF in vivo and/or is a substrate for nitric oxide synthase. The methods can further comprise administering a therapeutically effective amount of at least one therapeutic agent. Alternatively, the methods for treating and/or preventing cardiovascular diseases and disorders, can comprise administering a therapeutically effective amount of at least one taxane, at least one therapeutic agent, and, optionally, at least one compound that donates, transfers or releases nitric oxide as a charged species, i.e., nitrosonium (NO+) or nitroxyl (NOxe2x88x92), or as the neutral species, nitric oxide (NOxe2x80xa2), and/or stimulates endogenous production of nitric oxide or EDRF in vivo and/or is a substrate for nitric oxide synthase. The taxanes, the nitric oxide donors, and the therapeutic agents can be administered separately or as components of the same composition in one or more pharmaceutically acceptable carriers.
Yet another embodiment of the present invention describes methods for the prevention of platelet aggregation and platelet adhesion caused by the exposure of blood to a medical device or instrument by incorporating at least one nitrosated and/or nitrosylated taxane that is capable of releasing a therapeutically effective amount of nitric oxide into and/or on the portion(s) of the medical device that come into contact with blood (including blood components and blood products) or vascular tissue. The methods can further comprise incorporating at least one compound that donates, transfers or releases nitric oxide, and/or stimulates endogenous production of nitric oxide or EDRF in vivo and/or is a substrate for nitric oxide synthase, and, optionally, at least one therapeutic agent into and/or on the portion(s) of the medical device that come into contact with blood or vascular tissue. Alternatively the methods can comprise incorporating at least one taxane and at least one NO donor, and, optionally, at least one therapeutic agent.
Another embodiment of the invention relates to the local administration of at least one taxane, that is optionally substituted with at least one NO and/or NO2 group, and, optionally, at least one therapeutic agent and/or at least one nitric oxide donor, to treat injured tissue, such as damaged blood vessels.
The present invention also provides methods using the compounds and compositions described herein to prevent or treat autoimmune diseases, pathological conditions resulting from abnormal cell proliferation, polycystic kidney disease, inflammatory diseases, to preserve organs and/or tissues, or to inhibit wound contraction, by administering to a patient in need thereof a therapeutically effective amount of at least one of the compounds and/or compositions described herein. In these methods, the taxanes that are optionally nitrosated and/or nitrosylated, nitric oxide donors and therapeutic agents can be administered separately or as components of the same composition in one or more pharmaceutically acceptable carriers.
These and other aspects of the present invention are described in detail herein.